Targeting Periplakin of Novel Benzenesulfonamides as Highly Selective Agonists for the Treatment of Vitiligo

  • J Med Chem. 2024 Nov 14;67(21):19323-19341. doi: 10.1021/acs.jmedchem.4c01717.
Hui Zhong  1 ,  Panpan Li  1 ,  Qiuming Yan  2 ,  Yu Xia  2 ,  Xin Zhang  2 ,  Yifan Lai  1 ,  Liqiang Li  1 ,  Feifei Wang  1 ,  Jing Shang  1 ,  Xiaoming Zha  2
Affiliations
  • 1. School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • 2. School of Engineering, China Pharmaceutical University, Nanjing 211198, China.
PMID: 39485487 DOI: 10.1021/acs.jmedchem.4c01717
Abstract

Vitiligo is the most common cause of depigmentation worldwide, with immunosuppressive treatments often being inefficient and prone to recurrence, making it essential to identify new therapeutic targets. Periplakin (PPL) has been identified and confirmed as a key factor in vitiligo-related depigmentation. Based on this, a series of selective PPL agonists, specifically benzenesulfonamides, have been developed. Among these, compound I-3 exhibits superior efficacy compared to ruxolitinib, the only FDA-approved treatment for vitiligo. I-3 has been shown to increase cAMP levels by regulating PPL, which enhances MITF expression, a key transcription factor in melanin biosynthesis. Additionally, I-3 promotes melanin production by regulating tryptophan metabolism. In summary, PPL is a promising drug target, and I-3 has strong potential for future treatment of vitiligo due to its high selectivity and favorable druggability.

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